Niemann-Pick Disease

1
Niemann-Pick Disease

• Maggie W. George
• December 5, 2005

2
The Disease

• Condition involving the breakdown and use of fats
  and cholesterol in the body
• Harmful amounts of lipids accumulate in the
  spleen, liver, lungs, bone marrow, and brain
• Autosomal recessive pattern of inheritance (two
  copies of the gene must be present)
• Four variants A, B, C1, and C2
• Clinical feature include severe liver disease,
  breathing difficulties, developmental delay,
  seizures, increased muscle tone, lack of
  coordination, problems feeding, and inability to
  move eyes vertically.
• No treatment

3
Variants

• Types A and B mutated SMPD1 gene
• SMPD gene carries instructions for cells to
  produce, sphingomyelinase, which processes
  lipids.
• Mutations lead to deficiency of sphingomyelinase
  and accumulations of cholesterol and lipids.
• Types C1 and C2 mutated NCP1 or NCP2 gene
• NCP1 gene produces a protein involved in the
  movement of cholesterol and lipids within a cell.
• May be a cholesterol pump, which is why its
  mutation leads to the buildup of lipids and
  cholesterol in the cell membrane.
• Plays a critical role in regulation of
  intracellular cholesterol trafficking
• NCP2 gene produces protein that binds and
  transports cholesterol (not fully understood).

4
NCP1 v. NCP2 Gene

• 95 of patients have mutations in the NPC1 gene
• Mapped at chromosome 18q11
• NPC1 encodes a 1278 amino acid glycoprotein with
  13 transmembrane domains.
• Remainder of patients have mutations in the NPC2
  gene (or HE1 gene)
• Mapped at chromosome 14q24.3
• Encodes a small soluble lysosomal protein
  involved in cholesterol binding.
• Both genes have identical biochemical patterns
  suggesting that the two proteins function
  together in cellular transport of cholesterol,
  glycolipids, etc.
• Work together to facilitate the intracellular
  transport of lipids from the lysosome to other
  cellular sites.
• Their precise functions and relationship remain
  unclear and are currently the subject of intense
  investigation.

5
NCP1 Mutations

• Over 130 mutations have been identified in NPC1
• Results in Niemann-Pick Disease Type C1
• Most found within a NPC1 specific cysteine-rich
  domain, suggesting that the integrity of this
  region is crucial for normal functioning of the
  protein.
• Mutations include missense mutations, small
  deletions that generate premature stop codons,
  intronic mutations predicted to alter splicing,
  and point mutations.
• Specific mutation examples
• exon 20 c.2932 CgtT
• c.882-28 AgtG (note that patients with this
  mutation had fibroblasts containing small amounts
  of mRNA without exon 7)
• point mutation in exon 20 (causing frameshift and
  premature stop codon)
• 1553G-A transition (causing a splicing error of
  exon 9)
• 2783A-C transversion that results in a
  gln928-to-pro amino acid substitution
• 3263A-G transition leading to a tyr1088-to-cys
  amino acid substitution
• 530G-A change in exon 5, resulting in a
  cys177-to-tyr substitution
• 4-bp deletion, TTAC

6
NCP2 Mutations

• Results in Niemann-Pick Disease Type C2 and
  frontal lobe atrophy
• Single amino acid changes prevents both
  cholesterol binding and the restoration of normal
  cholesterol levels in mutant cells.
• Specific mutation examples 16 mutant alleles
  were identified representing only 5 different
  mutations (all had a severe impact on the
  protein)
• 2 nonsense mutations, glu20 to ter (E20X)
  associated with severe rapid disease course
• Results in a frameshift in exon 2, which
  generates a stop codon 4 codons downstream of
  frameshift
• Lung involvement ? death from respiratory failure
• Glu118 to ter substitution (E118X)
• Result of a G-to-T transversion at nucleotide 352
  in exon 1 of HE1 gene
• 1-bp deletion (27delG)
• Splice mutation (IVS25G-A) very difference
  clinical presentation
• Milder phenotype
• Childhood onset of neurologic symptoms but
  prolonged survival
• Missense mutation (S67P) ? resulting in reduced
  amts of abnormal HE1 protein.
• E20X was established as the most common mutant
  allele (56 frequency)

7
Lack of Knowledge

• Unfortunately, the NCP1 and the NCP2 gene are not
  fully understood, which means there is no
  proposed structure for either.
• There is a structure for the NCP2 bovine gene,
  but then again there is little information about
  the actual mutations involved.

8
Human to Bovine Relationship
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References

• http//en.wikipedia.org/wiki/Niemann-Pick_disease
• http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd
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• http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbP
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• http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbP
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• http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbp
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